Despite aggressive treatment with surgery, combination chemotherapy with stem cell rescue, and in some cases radiation, young children with malignant brain tumors have a 5-year event-free survival rate of 15-30%. A critical barrier to more effective and less toxic therapies for these children is the paucity of functional knowledge about the molecular pathways that are critical for survival of these age-specific tumors. Furthermore, the incidence of infant and toddler brain tumors is low enough that they are orphan diseases, which attract no appreciable industry interest. In this proposal, we bring together some of the world's leading experts on high throughput RNAi assays to identify candidate therapeutic targets with an innovative new approach to test and prioritize potentially synergistic combination therapies and a highly experienced brain tumor translational research team to solve the specific clinical problem that highly aggressive therapies are failing to improve outcomes in infants and toddlers with brain tumors. Our broad, long-term goal is to double the cure rate for infants and toddlers with brain cancer.
Our specific aims are 1) To assess the efficacy of Cdk 4/6 inhibition in clinically relevant mouse models of ATRT and medulloblastoma;2) To identify novel therapeutic targets in infant and toddler brain tumors;3) To advance one highly effective drug combination to the point of human clinical trials for infants and toddlers with brain tumors. The expected outcome is a combination therapy regimen that produces durable remission in established, bulky, clinically relevant mouse models of infant and toddler brain cancer. The significance of this work is that pediatric neuro-oncologists will abandon the highly toxic and ineffective therapeutic regimens that we are currently using in favor of a targeted approach that has higher efficacy and less toxicity.

Public Health Relevance

This proposal integrates drug target identification and an innovative approach to prioritizing highly effective combinations of cancer drugs to advance more effective and less toxic therapy regimens for infants and toddlers with brain tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA155360-01
Application #
8027914
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Forry, Suzanne L
Project Start
2011-06-07
Project End
2016-03-31
Budget Start
2011-06-07
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$365,200
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Xu, Tao; Zhang, Honglai; Park, Sung-Soo et al. (2017) Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis. Neoplasia 19:216-225
Crook, Zachary R; Sevilla, Gregory P; Friend, Della et al. (2017) Mammalian display screening of diverse cystine-dense peptides for difficult to drug targets. Nat Commun 8:2244
Ding, Yu; Herman, Jacob A; Toledo, Chad M et al. (2017) ZNF131 suppresses centrosome fragmentation in glioblastoma stem-like cells through regulation of HAUS5. Oncotarget 8:48545-48562
Klinghoffer, Richard A; Bahrami, S Bahram; Hatton, Beryl A et al. (2015) A technology platform to assess multiple cancer agents simultaneously within a patient's tumor. Sci Transl Med 7:284ra58
Toledo, Chad M; Ding, Yu; Hoellerbauer, Pia et al. (2015) Genome-wide CRISPR-Cas9 Screens Reveal Loss of Redundancy between PKMYT1 and WEE1 in Glioblastoma Stem-like Cells. Cell Rep 13:2425-2439
Herman, Jacob A; Toledo, Chad M; Olson, James M et al. (2015) Molecular pathways: regulation and targeting of kinetochore-microtubule attachment in cancer. Clin Cancer Res 21:233-9
Kumar, Akash; Boyle, Evan A; Tokita, Mari et al. (2014) Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes. Genome Biol 15:530
Gottardo, Nicholas G; Hansford, Jordan R; McGlade, Jacqueline P et al. (2014) Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group. Acta Neuropathol 127:189-201
Toledo, Chad M; Herman, Jacob A; Olsen, Jonathan B et al. (2014) BuGZ is required for Bub3 stability, Bub1 kinetochore function, and chromosome alignment. Dev Cell 28:282-94
Shih, David J H; Northcott, Paul A; Remke, Marc et al. (2014) Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol 32:886-96

Showing the most recent 10 out of 21 publications